Several laboratories using different model systems have approached understanding why alpha-synuclein is toxic to cells. Our approach has been to develop a mammalian system where we can induce alpha-synuclein protein over several days with the long term goal of then finding genes that can block the effect. In parallel, we made cell lines expressing tau. Despite several previous publications supporting an acute toxic effect, we have fairly modest toxicity in our model. We are therefore addressing different strategies to recover modifiers. These include testing genes that are reported to worsen alpha-synuclein toxicity from previous papers, trying different measures of toxicity, and increasing the length of time for which toxic proteins are expressed.